Not Applicable
Not Applicable
1. Field of the Invention
The present invention concerns new processes for the preparation of 5-(2-oxazolylalkylthio)-2-azacycloalkanoylaminothiazoles and analogs, inhibitors of cyclin dependent kinases.
2. Description of the Related Art
The 5-(2-oxazolylalkylthio)-2-azacycloalkanoylaminothiazole compounds of formula I 
or a pharmaceutically acceptable salt thereof, wherein:
R is alkyl, aryl or heteroaryl;
R1, R2, R3, R4 and R5 are each independently hydrogen, alkyl, aryl or heteroaryl;
R6 and R7 are each independently hydrogen, alkyl, aryl, heteroaryl, halogen, hydroxy or alkoxy;
R8 is hydrogen, alkyl, aryl, heteroaryl, CONR9R10, COR11 or COOR12;
R9, R10, R11 and R12 are each independently hydrogen, alkyl or aryl;
m equals 0 to 5; and
n equals 0 to 5,
are novel, potent inhibitors of cyclin dependent kinases (cdks). They are useful in the therapy of proliferative diseases, for example, cancer, inflammation, autoimmune diseases such as arthritis, viral diseases, fungal diseases, chemotherapy-induced alopecia, neurodegenerative disorders such as Alzheimer""s disease and cardiovascular disease. More specifically, the compounds of formula I are useful in the treatment of a variety of cancers such as bladder, breast, colon, kidney, liver and lung cancers.
WO 9924416 and corresponding U.S. Pat. No. 6,040,321 describe the preparation of 5-(2-oxazolylalkylthio)-2-aminothiazoles, key intermediates in the synthesis of 5-(2-oxazolylalkylthio)-2-azacycloalkanoylaminothiazoles of formula I, by reacting 5-acetylthio-2-acetylaminothiazole with a base followed by trapping the thiolate with a 2-oxazolylalkyl halide. Hydrolysis of the resulting 5-(2-oxazolylalkylthio)-2-acetylaminothiazole compounds afforded the 5-(2-oxazolylalkylthio)-2-aminothiazole key intermediates. The requisite 2-oxazolylalkyl halides were prepared by (i) reaction of xcex2-hydroxy amines with xcex1-chloroacyl chlorides followed by oxidation of the resulting xcex2-hydroxy-xcex1-chloroamides and subsequent oxazole ring formation (K. S. Kim et al., WO 9924416, May 20, 1999) or (ii) reaction of xcex1-diazo ketones with xcex1-chloronitriles (K. S. Kim et al, WO 9924416, May 20, 1999; T. Ibata et al., Bull. Chem. Soc. Japan 1979, 52, 3597). Although a variety of 5-(2-oxazolylalkylthio)-2-aminothiazoles can be prepared by this method, this process is not amenable to large scale synthesis due to the commercial availability of the starting 5-acetylthio-2-acetylaminothiazole, the use of hazardous xcex1-diazo ketones and expensive chromatographic separation of products.
Reaction of xcex1-halo ketones with azide to give xcex1-azido ketones has been previously reported in the literature (A. Hassner et al., Angew Chem. Int. Ed. Engl. 1986, 25, 478; M. G. Nair et al., J. Med. Chem. 1980, 23, 899; H.-J. Ha et al., Synth. Commun. 1994, 24, 2557). Reaction of xcex1-sulfonyloxy ketones with azide to give xcex1-azido ketones has also been previously reported (T. Patonay et al., J. Org. Chem. 1994, 59, 2902; G. A. Revelli et al, Synth. Commun. 1993, 23, 1111).
Reduction of xcex1-azido ketones to xcex1-amino ketones has been described in the literature (H.-J. Ha et al., Synth. Commun. 1994, 24, 2557; J. P. Sanchez et al., J. Heterocycl. Chem. 1988, 25, 469; S. K. Boyer et al., J. Org. Chem. 1985, 50, 3408). Reaction of xcex1-amino ketones with xcex1-halo acyl halides to give the corresponding amides has further been described (G. T. Newbold et al., J. Chem. Soc. 1948, 1855; G. T. Newbold et al., J. Chem. Soc. 1950, 909).
Reaction of alkylthiouronium salts with alkyl halides to give sulfides has been previously reported (H. Chen et al., Synth. Commun. 1990, 20, 3313). Reaction of alkylthiols with 5-bromo-2-aminothiazole to give 5-alkylthio-2-aminothiazoles has been reported (J. B. Dickey et al., J. Org. Chem. 1959, 24, 187).
This invention concerns new efficient processes for the preparation of 5-(2-oxazolylalkylthio)-2-aminothiazoles. The processes involve new strategies for the preparation of 2-oxazolylalkyl halides and 5-(2-oxazolylalkylthio)-2-aminothiazoles which include the method of making new key intermediate quaternary ammonium salts and 2-oxazolylalkyl sulfide derivatives. This invention further relates to processes for the preparation of 5-(2-oxazolylalkylthio)-2-azacycloalkanoylaminothiazoles and analogs, inhibitors of cyclin dependent kinases.
Not Applicable